Aspartic protease inhibitors

Abstract

The present invention provides a compound of formula (I) wherein a, b, c, d, and e, are R7, OR7, SR7, NR7R8, NHCOR7, CO2R7, CN, NO2, NH2, N3, or a halogen. R7 and R8 are H or alkyl, R1 and R2 are H or alkyl, and R3 is a non-aromatic substituent. Substituent A is OH, NH2, or SH. Substituents B and B1 include amide and sulfonamide groups, which can be cyclic, acyclic, or amino acid derivatives. Alternatively, B and R' together with the nitrogen to which they are bonded, and/or B' and R2 together with the nitrogen to which they are bonded, define a heterocycle. The present invention further provides a pharmaceutical composition that includes a carrier and a therapeutically effective amount of at least one compound of the present invention. The present invention further provides therapeutic methods that include administering a therapeutically effective amount of at least one compound of the present invention

What is claimed is:  
     
       1. A compound of the formula:                    
       wherein: 
       a, b, c, d, and e, are the same or different and each is H, R 7 , OR 7 , SR 7 , NR 7 R 8 , NHCOR 7 , CO 2 R 7 , CN, NO 2 , NH 2 , N 3 , or a halogen, wherein R 7  and R 8  are the same or different and each is H, an unsubstituted C 1 -C 20  alkyl, or a substituted C 1 -C 20  alkyl;  
       R 1  and R 2  are the same or different and each is H or a C 1 -C 20  alkyl, wherein R 1  and R 2  are unsubstituted or substituted;  
       R 3  is isopropyl, wherein R 3  is unsubstituted or substituted;  
       A is OH, NH 2 , or SH;  
       B and B′ are the same or different and each is of the formula:                    
        wherein:  
       m, n, and z, are the same or different and each is an integer from 0 to 4;  
       Q is SO 2  or C═(X), wherein X is O, NR 7 , NCO 2 R 7 , NSO 2 R 7 , or S;  
       Y is O, S, NR 4 , a C 6 -C 15  aryl, or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein R 4  is H, a C 1 -C 20  an alkyl, a C 2 -C 20  alkenyl, a C 2 -C 20  alkynyl, a cycloalkyl having from 3 to about 10 carbon atoms in the carbocyclic skeleton thereof, a heterocycloalkyl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, a phenyl, a naphthyl, or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein R 4  is unsubstituted or substituted, and, when Y is an aryl or a heteroaryl, it is unsubstituted or substituted;  
       R 5  is H, a C 1 -C 20  alkyl, a C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, a cycloalkyl having from 3 to about 10 carbon atoms in the carbocyclic skeleton thereof, a heterocycloalkyl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, a phenyl, a naphthyl, or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein R 5  is unsubstituted or substituted;  
       L is O, S, or NH;  
       R 6  is H, a C 1 -C 20  alkyl, a C 2 -C 20  alkenyl, a C 2 -C 20  alkynyl, a cycloalkyl having from 3 to about 10 carbon atoms in the carbocyclic skeleton thereof, a heterocycloalkyl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, a phenyl, a naphthyl, or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein R 6  is unsubstituted or substituted; and  
       W of formula (If) is an organic residue comprising at least one carbon atom and at least one heteroatom, wherein W shares at least two bonds with the nitrogen atom bonded thereto such that the substituent:                    
        of formula (If) defines a heterocycle, having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, which is unsubstituted or substituted; and  
       E is H, (CH 2 ) q R 9 , O(CH 2 ) q R 9 , S(CH 2 ) q R 9 , N[(CH 2 ) q R 9 ]R 10 , CO(CH 2 ) q R 9 , CS(CH 2 ) q R 9 , CO 2 (CH 2 ) q R 9 , NHCO 2 (CH 2 ) q R 9 , C(O)S(CH 2 ) q R 9 , C(S)O(CH 2 ) q R 9 , CS 2 (CH 2 ) q R 9 , C(O)N[(CH 2 ) q R 9 ]R 10 , NHC(O)N[(CH 2 ) q R 9 ]R 10 , C(S)N[(CH 2 ) q R 9 ]R 10 , NHC(S)N[(CH 2 ) q R 9 ]R 10 , NR 10 CO(CH 2 ) q R 9 , NR 10 CS(CH 2 ) q R 9 , NR 10 CO 2 (CH 2 ) q R 9 , NR 10 C(O)S(CH 2 ) q R 9 , NR 10 CS 2 (CH 2 ) q R 9 , O 2 C(CH 2 ) q R 9 , S 2 C(CH 2 ) q R 9 , SCO(CH 2 ) q R 9 , OCS(CH 2 ) q R 9 , SO 2 (CH 2 ) q R 9 , OSO 2 (CH 2 ) q R 9 , NR 10 SO 2 (CH 2 ) q R 9 , CN, NO 2 , N 3 , or a halogen, wherein:  
       q is an integer from 0-4;  
       R 9  is a C 1 -C 20  alkyl, a C 2 -C 20  alkenyl, a C 2 -C 20  alkynyl, a cycloalkyl having from 3 to about 10 carbon atoms in the carbocyclic skeleton thereof, a heterocycloalkyl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, a phenyl, a naphthyl, or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein R 9  is unsubstituted or substituted; and  
       R 10  is H, an unsubstituted C 1 -C 20  alkyl, or a substituted C 1 -C 20  alkyl; or  
       B and R 1  together with the nitrogen atom to which they are bonded, and/or B′ and R 2  together with the nitrogen atom to which they are bonded, comprise a heterocycle, having 6 atoms in the ring skeleton thereof, of the formula:                    
        wherein W and E are as defined herein and said heterocycle is unsubstituted or substituted, wherein:  
       when R 1 , R 2  and/or R 4  is substituted, each is substituted with one or more substituents selected from the group consisting of R 7 , OR 7  SR 7 , NR 7 R 8 , CN, NO 2 , N 3 , and halogens;  
       when R 3  is substituted, it is substituted with one or more substituents selected from the group consisting of OR 7 , SR 7 , CN, NR 7 R 8 , NO 2 , N 3 , and halogens;  
       when Y and/or R 5  is substituted, it is substituted with one or more substituents selected from the group consisting of, R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 7 , NR 8 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 , SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , a guanidyl, CN, NO 2 , N 3 , and halogens;  
       when R 6  is substituted, it is substituted with one or more substituents selected from the group consisting of R 7 , OR 7 , SR 7 , CO 2 R 7 , SO 2 R 7 , NR 7 R 8 , CN, NO 2 , N 3 , a cycloalkyl having from 3 to about 10 carbon atoms in the carbocyclic skeleton thereof, a heterocycloalkyl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, a phenyl, a naphthyl, or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, and halogens;  
       when W of formula (If), the heterocycle defined by B and R 1  together with the nitrogen atom to which they are bonded, and/or the heterocycle defined by B′ and R 2  together with the nitrogen atom to which they are bonded, are substituted, each is substituted with one or more substituents selected from the group consisting of oxo, thio, R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(O)SR 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 7 , NR 8 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 , SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , CN, NO 2 , N 3 , and halogens,  
       when R 1  and/or R 8  are substituted, each is substituted with one or more halogen atoms;  
       when R 9  is substituted, it is substituted with one or more substituents selected from the group consisting of R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(O)SR 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 7 , NR 8 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 , SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , a guanidyl, oxo, thio, CN, NO 2 , N 3 , and halogens; and  
       when R 10  is substituted, it is substituted with one or more substituents selected from the group consisting of CN, NH 2 , NO 2 , N 3 , and halogens;  
       or a pharmacologically acceptable salt thereof. 
     
     
       2. The compound of  claim 1 , wherein a, b, c, d, e, R 1 , and R 2  are H, and A is OH. 
     
     
       3. The compound of  claim 1 , wherein at least one of B and B′ is:                    
     
     
       4. The compound of  claim 3 , wherein Q is C═O, Y is O or S, m and n are the same or different and each is 0 or 1, and E is R 9 . 
     
     
       5. The compound of  claim 4 , wherein Y is O, and at least one of B or B′is:                    
       wherein R 9  is a heterocycloalkyl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, a phenyl, a naphthyl, or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein R 9  is unsubstituted or is substituted with one or more substituents selected from the group consisting of R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(O)SR 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 8 , NR 7 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 , SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , a guanidyl, CN, NO 2 , N 3 , and halogens, wherein R 7  and R 8  are the same or different and each is H, an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more halogen atoms. 
     
     
       6. The compound of  claim 5 , wherein R 9  is selected from the group consisting of 2-methylphenyl, 2,6-dimethylphenyl, 3-amino-2-methylphenyl, 3-acetamido-2-methylphenyl, 3-hydroxy-2-methylphenyl, 4-hydroxy-2-methylphenyl, 4-amino-2-methylphenyl, 3-acetamido-2-methylphenyl, 4-methoxy-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-trifluoromethyl-2-methylphenyl, 2,4-dimethylphenyl, 2-methyl-4-nitrophenyl, 3-amino-2,6-dimethylphenyl, 3-hydroxy-2,6-dimethylphenyl, 2-methyl-3-nitrophenyl, 4-acetyl-2-methylphenyl, 4-aminocarbonyl-2-methylphenyl, benzopiperazinyl, tert-butyl, hydroxy tert-butyl, and morpholinyl. 
     
     
       7. The compound of  claim 1 , wherein B or B′ is:                    
     
     
       8. The compound of  claim 7 , wherein B or B′ is of formula (Ic), Q is C═O, n is 0 and E is R 9 , wherein R 9  is a heterocycloalkyl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof. 
     
     
       9. The compound of  claim 8 , wherein R 9  is a morpholinyl substituent. 
     
     
       10. The compound of  claim 7 , wherein: 
       z is 0 or 1;  
       R 5  is an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more substituents selected from the group consisting of R 7 , OR 7  and C(O)NR 7 R 8 ;  
       R 6  is H;  
       Q is C═O;  
       Y is O or S;  
       m and n are the same or different and each is 0 or 1; and  
       E is R 9 , wherein R 9  is a phenyl, a naphthyl or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein R 9  is unsubstituted or is substituted with one or more substituents selected from the group consisting of R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(O)SR 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 7 , NR 8 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 , SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , a guanidyl, CN, NO 2 , N 3 , and halogens;  
       wherein R 7  and R 8  are the sane or different and each is H, an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more halogens.  
     
     
       11. The compound of  claim 10 , wherein B or B′ is of the formula (Id), wherein z is 0, R 5  is isopropyl, Y is O, m is 1, and n is 0, such that B or B′ is:                    
       wherein R 9  is phenyl, which is unsubstituted or is substituted with one or more substituents selected from the group consisting of R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(O)SR 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 7 , NR 8 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 , SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , a guanidyl, CN, NO 2 , N 3 , and halogens, wherein R 7  and R 8  are the same or different and each is H, an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more halogens. 
     
     
       12. The compound of  claim 1 , wherein B or B′ is of the formula (Ie), wherein L i's NH, z is 0, and R 5  is isopropyl such that B or B′ is:                    
       wherein E is H, COR 9 , or SO 2 R 9 , wherein R 9  is methyl. 
     
     
       13. The compound of  claim 1 , wherein B or B′ is:                    
       wherein the heterocycle:                    
       of formula (If) is unsubstituted or substituted with one or more substituents selected from the group consisting of R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(O)SR 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 7 , NR 8 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 ; SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , CN, NO 2 , N 3 , and halogens, wherein R 7  and R 8  are the same or different and each is H, an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more halogen atoms. 
     
     
       14. The compound of  claim 13 , wherein W is of the formula —(CH 2 ) 2 O(CH 2 ) 2 —, —(CH 2 ) 2 S(CH 2 ) 2 —, —(CH 2 ) 2 SO(CH 2 ) 2 —, —(CH 2 ) 2 SO 2 (CH 2 ) 2 —, or —(CH 2 ) 2 NH(CH 2 ) 2 —, wherein W is unsubstituted or substituted. 
     
     
       15. The compound of  claim 13 , z is 0, R 5  is isopropyl, and W of formula (If) is an organic residue that defines a heterocycle such that B or B′ is of the formula:                    
       wherein said heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of R 7 , OR 7 , SR 7 , NR 7 R 8 , COR 7 , CSR 7 , CO 2 R 7 , C(O)SR 7 , C(S)OR 7 , CS 2 R 7 , C(O)NR 7 R 8 , NHC(O)NR 7 R 8 , C(S)NR 7 R 8 , NHC(S)NR 7 R 8 , NR 8 COR 7 , NR 8 CSR 7 , NR 8 CO 2 R 7 , NR 8 C(O)SR 7 , NR 8 CS 2 R 7 , O 2 CR 7 , S 2 CR 7 , SCOR 7 , OCSR 7 , SO 2 R 7 , OSO 2 R 7 , NR 8 SO 2 R 7 , CN, NO 2 , N 3 , and halogens, wherein R 7  and R 8  are the same or different and each is H, an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more halogen atoms. 
     
     
       16. The compound of  claim 3 , wherein B or B′ is:                    
       wherein: 
       Q is SO 2  or C═O;  
       m and n are the same or different and are each 0 or 1; and  
       Y is a C 6 -C 15  aryl or a heteroaryl having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, wherein Y is unsubstituted or substituted.  
     
     
       17. The compound of  claim 16 , wherein Q is C═O; m and n are 0; and Y is an unsubstituted phenyl or a substituted phenyl such that B or B′ is:                    
       wherein E is H, NR 9 R 10 , NHCO 2 (CH 2 ) q R 9 , NHC(O)N[(CH 2 ) q R 9 ]R 10 , NHC(S)N[(CH 2 ) q R 9 ]R 10 , NR 10 CO[(CH 2 ) q R 9 ], NR 10 CS[(CH 2 ) q R 9 ], NR 10 CO 2 [(CH 2 ) q R 9 ], NR 10 C(O)S[(CH 2 ) q R 9 ], NR 10 CS 2 [(CH 2 ) q R 9 ], NR 10 SO 2 [(CH 2 ) q R 9 ], CN, NO 2 , N 3 , or a halogen. 
     
     
       18. The compound of  claim 17 , wherein E is NHCO 2 (CH 2 ) q R 9 , wherein q is 0 or 1, and R 9  is a phenyl. 
     
     
       19. The compound of  claim 1 , wherein B is bonded to the nitrogen atom bearing R 1  via an amide bond and is selected from the group consisting of:                    
       wherein B′ is bonded to the nitrogen bearing R 2  via an amide bond and is selected from the group consisting of:                  
                   
     
     
       20. The compound of  claim 1 , wherein B and B′ are the same or different and each is bonded to the nitrogen bearing R 1  and R 2 , respectively, via an amide bond, and each is selected from the group consisting of:                  
                   
       wherein R 7  is H, an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more halogens, wherein each occurrence of R 7  is the same or different when said compound is substituted with two or more R 7  substituents. 
     
     
       21. The compound of  claim 20 , wherein B and B′ are the same or different and each is of the formula:                    
       wherein R 7  is H, an unsubstituted C 1 -C 20  alkyl or a C 1 -C 20  alkyl substituted with one or more halogens and each occurrence of R 7  on said compound is the same or different. 
     
     
       22. The compound of  claim 1 , wherein B and R 1  together with the nitrogen atom to which they are bonded comprise a heterocycle, having 6 atoms, at least two of which are heteroatoms, in the ring skeleton thereof, of the formula:                    
       such that said compound is of the formula:                    
     
     
       23. The compound of  claim 22 , wherein W is of the formula —(CH 2 ) 2 O(CH 2 ) 2 —, —(CH 2 ) 2 S(CH 2 ) 2 —, —(CH 2 ) 2 SO(CH 2 ) 2 —, —(CH 2 ) 2 SO 2 (CH 2 ) 2 —, or —(CH 2 ) 2 NH(CH 2 ) 2 —, wherein W is unsubstituted or substituted. 
     
     
       24. The compound of  claim 1 , wherein B′ and R 2  together with the nitrogen atom to which they are bonded comprise a heterocycle, having 6 atoms in the ring skeleton thereof, of the formula:                    
       such that said compound is of the formula:                    
     
     
       25. The compound of  claim 24 , wherein W is of the formula —(CH 2 ) 2 O(CH 2 ) 2 —, —(CH 2 ) 2 S(CH 2 ) 2 —, —(CH 2 ) 2 SO(CH 2 ) 2 —, —(CH 2 ) 2 SO 2 (CH 2 ) 2 —, or —(CH 2 ) 2 NH(CH 2 ) 2 —, wherein W is unsubstituted or substituted. 
     
     
       26. A composition comprising a carrier and a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
       27. A method of treating an HIV infection comprising administering a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
       28. A method of treating cancer comprising administering a cathepsin D inhibiting-effective amount of at least one compound of  claim 1 . 
     
     
       29. The method of  claim 28 , wherein said cancer is breast cancer. 
     
     
       30. A method of treating a malarial infection comprising administering a plasmepsin inhibiting-effective amount of at least one compound of  claim 1 . 
     
     
       31. A compound having the core structure:                    
       wherein 
       a, b, c, d, and e, are the same or different and each is H, R 7 , OR 7 , SR 7 , NR 7 R 8 , NHCOR 7 , CO 2 R 7 , CN, NO 2 , NH 2 , N 3 , or a halogen, wherein R 7  and R 8  are the same or different and each is H, an unsubstituted alkyl, or a substituted alkyl;  
       R 3  is isopropyl, wherein R 3  is unsubstituted or substituted; and  
       A is OH, NH 2 , or SH.